The Eastern Iowa Western Illinois Vascular Access Consortium (EIWIVAC) is a consortium of hemodialysis units surrounding the University of Iowa co-founded by a vascular biologist and an expert in clinical trials design to address the problem of vascular access failure. Hemodialysis vascular access failure is a frequent cause of morbidity and a major expense in caring for hemodialysis patients. The cause of access failure is neointimal hyperplasia leading to stenosis and thrombosis. This process occurs in both arteriovenous grafts (AVG) and native fistulas (AVF). The hypothesis underlying the present proposal is that pharmacological agents that inhibit vascular smooth muscle cell (vsmc) proliferation will decrease the neointimal hyperplasia and prolong vascular access survival. Both HMG CoA reductase inhibitors and dipyridamole have been shown to inhibit vascular smooth muscle cell proliferation. HMG CoA reductase inhibitors prevent the isoprenylation of small GTP binding proteins such as Ras that are needed for cell proliferation. Dipyridamole increases extracellular adenosine levels that can inhibit proliferation by unclear mechanisms. Studies from our lab have shown that combined treatment with these agents in low doses is additive or even synergistic at inhibiting vsmc proliferation. Therefore, we propose a randomized placebo controlled primary prevention trial using a factorial design to test whether treatment with either dipyridamole or an HMG CoA reductase inhibitor will increase primary survival of a newly created vascular access: either an AVG or an AVF. In addition, we briefly propose two additional trials. With access monitoring to detect stenosis before access failure, many prevalent accesses will require angioplasty. However, the restenosis rate after angioplasty is very high and resistant to many pharmacological agents. We propose in a second trial to test the hypothesis that the more potent antiproliferative effects of rapamycin in combination with an HMG CoA reductase inhibitor will inhibit the smooth muscle cell proliferation leading to restenosis. Finally, data shows that an upper arm native fistula (UAF) has superior survival to an AVG. However, the UAF appears to be underutilized in part because of concerns over high access flow rates and the possibility of increased heart failure and distal steal syndromes. While a randomized trial is not possible, we propose to establish a registry to examine the safety of a UAF compared to an AVG. If safety issues can be addressed, increased utilization of UAF may be the most cost-effective intervention.